Circadian Regulation of Antibiotic Resistance in the Microbiome

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Project Summary Humans must regulate a symbiotic relationship with almost 100 trillion intestinal bacteria which readily harbor antibiotic resistance genes and the mechanisms that spread them. Despite the relentless rise of antibiotic resistant infections little is known about the host factors that regulate antibiotic resistance development in vivo. Preliminary investigations revealed that the mammalian circadian clock may be such a factor. Prior in vivo studies have demonstrated that the circadian clock drives daily rhythms in microbiome composition which are synchronized to the day-night cycle. However, gene expression in the microbiome at circadian time scales is largely unexplored. To this end, a comprehensive study of the mouse microbiome was performed across the day-night light cycle. These data revealed that beyond daily rhythms of microbe abundances, extensive transcriptional rhythms occur in the microbiome across the day-night light cycle. Indeed, antibiotic resistance and horizontal gene transfer systems showed some of the most significant transcriptional rhythms in the microbiome, reaching peak expression within a 4-hour window each day. These preliminary data demonstrated that transcription in the microbiome is temporally structured in vivo. These diurnal (daily) rhythms are characteristic of regulation by the host’s circadian clock. Therefore, this proposal seeks to understand mechanisms driving diurnal bacterial transcription in the microbiome by examining the in vivo regulation of horizontal gene transfer and the impact of the host circadian clock on the spread of antibiotic resistance. Taken together, this work proposes the circadian clock synchronizes transcription in the microbiome to the day-night cycle, potentially revealing a mammalian regulator of antibiotic resistance development.